The inability of CNS neurons to regenerate their axons after injury places severe limitations on the functional recovery that can occur after traumatic injury, stroke, or certain neurodegenerative diseases. Regenerative failure has been attributed in part to proteins associated with CNS myelin and with glial scar that forms at an injury site. Several myelin inhibitors of axon growth, including the C-terminal of NogoA (Chen et al., 2000; GrandPre et al., 2000), myelin-associated glycoprotein, (McKerracher et al., 1994; Mukhopadhyay et al., 1994), and OMgp (Wang et al., 2002b), exert their effects via the Nogo receptor (NgR) and p75NTR or another co-receptor (Fournier et al., 2001; Domeniconi et al., 2002; Liu et al., 2002; Wang et al., 2002a,b). In culture, expression of NgR causes growth cones of embryonic chick retinal ganglion cells (RGCs) to collapse upon contact with the C-terminal region of Nogo (Nogo66) (Fournier et al., 2001) and inhibits neurite outgrowth from cerebellar granule cells on MAG, OMgp, or myelin (Wang et al., 2002a,b). Conversely, transfection with dominant-negative form of NgR (NgRDN) enables cerebellar granule cells in culture to overcome the inhibitory effects of myelin, Nogo66, OMgp, and MAG (Domeniconi et al., 2002; Wang et al., 2002a,b). However, the effects of overexpressing either NgR or NgRDN have not been investigated in vivo, nor have the effects of deleting the gene.
Antibodies to NogoA, or a small peptide inhibitor of NgR, increase corticospinal tract (CST) regeneration only to some extent in rats (Schnell et al., 1994; Bregman et al., 1995; GrandPre et al., 2002; Sicotte et al., 2003), whereas genetic deletion of the NogoA gene in mice results either in a modest CST regeneration (Kim et al., 2003b; Simonen et al., 2003) or in none (Zheng et al., 2003). Thus, overcoming specific myelin inhibitors, or suppression of signaling through NgR, is not sufficient to promote the substantive CNS regeneration in vivo that would be required for the treatment of neurological disorders (Steward et al., 2003; Woolf, 2003; Zheng et al., 2003).
There is a need in the art for methods and compositions that can improve the ability of a neuron, or portion of the nervous system, to regenerate, and to maintain desirable function, which can be used for treatment of neurological disorders.